AIDS dementia complex

Summary

AIDS dementia complex (MONDO:0020689) is a disease with 2 cohort genes (4 GWAS associations across 1 studies) and 34 clinical trials. Top therapeutic interventions include darunavir, mecamylamine, and ferumoxytol.

At a glance

• Cohort genes: 2
• GWAS associations: 4
• Clinical trials: 34

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	AIDS dementia complex
Mondo ID	MONDO:0020689
EFO	EFO:0002608
MeSH	D015526
NCIT	C2864
SNOMED CT	421529006
UMLS	C0001849
MedGen	177
GARD	0008250
Is cancer (heuristic)	no

Also known as: Acquired immune deficiency syndrome dementia complex · Acquired immune deficiency syndrome-related dementia · Acquired-Immune Deficiency Syndrome Dementia Complex · ADC · ADC - Acquired immune deficiency syndrome dementia complex · AIDS - Acquired immune deficiency syndrome dementia complex · AIDS dementia · AIDS dementia complex · AIDS Encephalopathies · AIDS Encephalopathy · AIDS RELAT DEMENTIA COMPLEX · AIDS related cognitive impairment · AIDS related Dementia Complex · AIDS with dementia (disorder) · AIDS-related Dementia Complex · Complex, AIDS Dementia · Complex, AIDS-related Dementia · Dementia associated with acquired immunodeficiency syndrome · Dementia associated with AIDS · DEMENTIA COMPLEX ACQUIRED IMMUNE DEFIC SYNDROME (+25 more)

Data availability: 4 GWAS associations (1 study).

Disease family

Classification path: disease › human disease › disease by developmental or physiological process › psychiatric disorder › cognitive disorder › dementia › AIDS dementia complex

Related subtypes (8): vascular dementia, Alzheimer disease, Lewy body dementia, hereditary dementia, dementia pugilistica, parkinsonism with dementia of Guadeloupe, progressive dementia with neuroserpin inclusion bodies, childhood-onset dementia

Genetics & variants

GWAS landscape

4 GWAS associations across 1 studies. Top hits map to 5 distinct genes (as reported by GWAS).

Top associations by p-value

rsID	p-value	Gene	Risk allele	Odds ratio
rs17154929	1e-07	LINC00841 - LINC03089	T
rs404005	3e-07	SLC8A1, SLC8A1-AS1	T
rs7996217	7e-07	NALCN	T
rs12742923	8e-07	LINC01362, LINC01725	T

Top studies (by case count)

Study	Lead author	Year	Cases	Controls	Title
GCST001542	Levine AJ	2012	0	0	Genome-wide association study of neurocognitive impairment and dementia in HIV-infected adults.

Variant details and genetic-evidence tiers

Tier distribution (top 50 variants)

Tier	Variants
Tier 1: coding	0
Tier 2: splice/UTR	0
Tier 3: regulatory	0
Tier 4: intronic/intergenic	4

MAF distribution

Bucket	Variants
common (>=0.05)	4
low_freq (0.01-0.05)	0
rare (<0.01)	0
unknown	0

Functional consequences

Consequence	Count
intron_variant	3
intergenic_variant	1

Top variants

rsID	Chr	Pos	Alleles	MAF	Consequence	Gene	p-value	Tier
rs17154929	10	44029227	C>T	0.05	intergenic_variant	LINC00841 - LINC03089	1e-07	Tier 4: intronic/intergenic
rs404005	2	40168938	C>T	0.05	intron_variant	SLC8A1, SLC8A1-AS1	3e-07	Tier 4: intronic/intergenic
rs7996217	13	101348594	T>C,G	0.05	intron_variant	NALCN	7e-07	Tier 4: intronic/intergenic
rs12742923	1	83024161	C>T	0.05	intron_variant	LINC01362, LINC01725	8e-07	Tier 4: intronic/intergenic

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 0 · Orphanet: 5 · OMIM-shared: 0 · Dual-evidence (GWAS+Mendelian): 0

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
NALCN	Orphanet:1146	Distal arthrogryposis type 1
NALCN	Orphanet:1147	Sheldon-Hall syndrome
NALCN	Orphanet:2053	Freeman-Sheldon syndrome
NALCN	Orphanet:562528	Congenital limbs-face contractures-hypotonia-developmental delay syndrome
NALCN	Orphanet:700336	Hypotonia-speech impairment-severe cognitive delay syndrome due to NALCN deficiency

Cohort genes → proteins

2 cohort genes, 2 distinct canonical proteins.

Evidence partition

Subset	Genes
gwas_only	2

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
SLC8A1	HGNC:11068	ENSG00000183023	P32418	Sodium/calcium exchanger 1	gwas
NALCN	HGNC:19082	ENSG00000102452	Q8IZF0	Sodium leak channel NALCN	gwas

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
SLC8A1	Sodium/calcium exchanger 1	Mediates the exchange of one Ca(2+) ion against three to four Na(+) ions across the cell membrane, and thereby contributes to the regulation of cytoplasmic Ca(2+) levels and Ca(2+)-dependent cellular processes.
NALCN	Sodium leak channel NALCN	Voltage-gated ion channel responsible for the resting Na(+) permeability that controls neuronal excitability.

Protein-family classification

Druggable: 1 · Difficult: 0 · Unknown: 1 · Druggable fraction: 0.5

Family distribution

Cohort families vs a genome-wide background (hypergeometric, BH-FDR; fold = observed/expected). Counts kept; sorted by enrichment, so the catch-all Other/Unknown bucket no longer leads.

Family	Genes	Fold	FDR
Ion channel	1	55.8×	0.036
Other/Unknown	1	0.9×	0.805

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
SLC8A1	Other/Unknown	no		DnaJ_domain, NaCa_exhngr1, Calx_beta
NALCN	Ion channel	yes		Ion_trans_dom, Volt_channel_dom_sf, NALCN

Expression context

Cohort genes with no expression data: 0.

2 cohort genes are a single-cell marker in ≥1 SCXA experiment.

Breadth distribution (Bgee present_calls)

Bucket	Genes
narrow (1-5 tissues)	0
moderate (6-20)	0
broad (>20)	2
unknown	0

Top tissues across cohort

Tissue	Cohort genes
adrenal tissue	1
endothelial cell	1
heart right ventricle	1
Brodmann (1909) area 23	1
corpus callosum	1
middle temporal gyrus	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
SLC8A1	249	ubiquitous	marker	heart right ventricle, adrenal tissue, endothelial cell
NALCN	201	ubiquitous	marker	middle temporal gyrus, Brodmann (1909) area 23, corpus callosum

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
NALCN	1,860
SLC8A1	1,658

Structural data

PDB: 2 · AlphaFold-only: 0 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
SLC8A1	P32418	5
NALCN	Q8IZF0	5

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 13. Enrichment computed across 2 evidence-associated genes (2 with Reactome annotation).

Pathways by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 2 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Sodium/Calcium exchangers	1	519.1×	0.009	SLC8A1
Reduction of cytosolic Ca++ levels	1	475.8×	0.009	SLC8A1
Platelet calcium homeostasis	1	356.9×	0.009	SLC8A1
Transport of small molecules	2	25.1×	0.009	SLC8A1, NALCN
Platelet homeostasis	1	139.3×	0.019	SLC8A1
Ion homeostasis	1	102.0×	0.021	SLC8A1
Stimuli-sensing channels	1	68.0×	0.025	NALCN
R-HSA-425393	1	64.9×	0.025	SLC8A1
Cardiac conduction	1	54.4×	0.026	SLC8A1
Ion channel transport	1	48.0×	0.027	NALCN
Muscle contraction	1	38.6×	0.030	SLC8A1
SLC-mediated transmembrane transport	1	29.6×	0.036	SLC8A1
Hemostasis	1	18.0×	0.055	SLC8A1

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 2 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
calcium ion transmembrane transport	2	210.7×	5e-04	SLC8A1, NALCN
sodium ion transmembrane transport	2	203.0×	5e-04	SLC8A1, NALCN
relaxation of smooth muscle	1	8426.0×	0.002	SLC8A1
calcium ion export	1	2106.5×	0.003	SLC8A1
vascular associated smooth muscle contraction	1	1685.2×	0.003	SLC8A1
positive regulation of synaptic transmission, cholinergic	1	1685.2×	0.003	NALCN
positive regulation of the force of heart contraction	1	1685.2×	0.003	SLC8A1
regulation of cell communication by electrical coupling	1	1203.7×	0.004	SLC8A1
negative regulation of intracellular signal transduction	1	1053.2×	0.004	SLC8A1
cellular response to caffeine	1	766.0×	0.004	SLC8A1
calcium ion transmembrane import into cytosol	1	766.0×	0.004	SLC8A1
membrane depolarization during cardiac muscle cell action potential	1	702.2×	0.004	SLC8A1
cell communication by electrical coupling involved in cardiac conduction	1	702.2×	0.004	SLC8A1
regulation of cardiac muscle contraction by calcium ion signaling	1	648.1×	0.004	SLC8A1
negative regulation of cytosolic calcium ion concentration	1	648.1×	0.004	SLC8A1
relaxation of cardiac muscle	1	648.1×	0.004	SLC8A1
regulation of resting membrane potential	1	648.1×	0.004	NALCN
calcium ion transport into cytosol	1	601.9×	0.004	SLC8A1
sodium ion export across plasma membrane	1	526.6×	0.004	SLC8A1
regulation of the force of heart contraction	1	495.6×	0.004	SLC8A1
positive regulation of synaptic transmission, GABAergic	1	495.6×	0.004	NALCN
regulation of cardiac conduction	1	421.3×	0.004	SLC8A1
calcium ion import	1	401.2×	0.004	SLC8A1
intracellular sodium ion homeostasis	1	383.0×	0.004	SLC8A1
response to muscle stretch	1	383.0×	0.004	SLC8A1
regulation of cardiac muscle contraction by regulation of the release of sequestered calcium ion	1	337.0×	0.005	SLC8A1
cardiac muscle cell development	1	312.1×	0.005	SLC8A1
sodium ion import across plasma membrane	1	312.1×	0.005	SLC8A1
calcium ion import across plasma membrane	1	271.8×	0.005	SLC8A1
regulation of heart rate	1	234.1×	0.006	SLC8A1

Therapeutics

Drugs indicated for this disease

0 approved, 2 in late-stage (phase 3) trials. Disease-direct ChEMBL indications, not inferred from the associated-gene cohort below.

Drug	Development status
Stavudine	Phase 3 (in late-stage trials)
Zidovudine	Phase 3 (in late-stage trials)

Earlier-phase candidates (phase 2, investigational — efficacy not yet established): Didanosine, Ferumoxytol, Maraviroc.

Drug target analysis

Approved (phase 4): 0 · Phase ≥3: 0 · Phased (≥1): 0 · Undrugged: 2

Druggability breadth: 1 of 2 evidence-associated genes (50%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
SLC8A1	0	0
NALCN	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

Cohort genes with ChEMBL bioactivity (full, sorted by assay count)

Symbol	Assays	Type breakdown
SLC8A1	9	Binding:8, Functional:1

Pharmacogenomics

Cohort genes with a PharmGKB record: 2; with CPIC/DPWG dosing guidelines: 0.

No cohort gene has a CPIC/DPWG genotype-guided dosing guideline (PharmGKB).

Chemical tractability of cohort targets

0 approved/phased compounds have measured bioactivity against a cohort gene (and aren’t yet in disease-level trials). This is a research / tractability signal, NOT a therapeutic recommendation — a bioactivity row often reflects off-target or screening binding (e.g. promiscuous kinase inhibitors against a cohort kinase), implying no disease mechanism.

Druggability pyramid

Cohort genes binned by druggability tier (high → low):

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	0
B	Phased (≥1) drug, not yet approved	0
C	Druggable family + PDB, no drug	1	NALCN
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	1	SLC8A1

Undrugged target profiles

2 cohort genes are undrugged. Ranked by ‘starting-point quality’ (assay depth + drugged-partner adjacency).

Symbol	ChEMBL assays	Drugged partners (top 3)
SLC8A1	9	—
NALCN	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 34.

Phase distribution (across all retrieved trials)

Phase	Trials
Not specified	13
PHASE3	5
PHASE2	5
PHASE4	4
PHASE1	4
PHASE1/PHASE2	2
PHASE2/PHASE3	1

Top trials by phase / activity

NCT	Phase	Status	Title
NCT01263938	PHASE4	COMPLETED	Modulation of Monocyte Activation by Atorvastatin in HIV Infection
NCT01600170	PHASE4	COMPLETED	Downmodulating Monocyte Activation for HIV-1 Associated Neurocognitive Disorders (HAND)
NCT02503462	PHASE4	TERMINATED	Effect of Cobicistat Versus Ritonavir Boosting on the Brain Permeation of Darunavir in HIV-infected Individuals
NCT02951559	PHASE4	UNKNOWN	SOLFAMU Study of Nasal Brushing Collected OLFActory MUcosa Samples in the Diagnosis of Human Encephalopathies
NCT00000702	PHASE3	COMPLETED	A Multicenter Placebo-Controlled Double-Blind Trial to Evaluate Azidothymidine (AZT) Treatment of the AIDS Dementia Complex and Central Nervous System (CNS) Human Immunodeficiency Virus (HIV) Infection
NCT00000709	PHASE3	COMPLETED	An Open Trial of Zidovudine (AZT) Treatment of the AIDS Dementia Complex in Patients With AIDS or Low CD4+ Lymphocyte Counts
NCT00002163	PHASE3	COMPLETED	A Phase III, Randomized, Double-Blind, Multicentre Study to Evaluate the Safety and Efficacy of 1592U89 in Patients With AIDS Dementia Complex
NCT00002246	PHASE3	COMPLETED	A Study to Evaluate the Use of Stavudine (d4T) to Treat AIDS Dementia Complex
NCT01599975	PHASE3	UNKNOWN	A Study Comparing Long-acting Methylphenidate (ConcertaTM) vs. Placebo in the Treatment of Memory Loss Due to HIV
NCT02159027	PHASE2/PHASE3	COMPLETED	Maraviroc and NeuroAIDS Pathogenesis
NCT05586581	PHASE1/PHASE2	RECRUITING	SV2A & TSPO PET Imaging Measures to Reveal Mechanisms of HIV Neuropathogenesis During Antiretroviral Therapy
NCT00000657	PHASE2	COMPLETED	Comparison of 2’,3’-Dideoxyinosine (Didanosine, ddI) and Zidovudine in Therapy of Patients With the AIDS Dementia Complex
NCT00000867	PHASE2	COMPLETED	A Study to Evaluate the Use of Memantine In Combination With Anti-HIV Drugs to Treat AIDS Dementia Complex (ADC)
NCT02128828	PHASE2	COMPLETED	Effect of Cenicriviroc on HIV Neurocognitive Impairment
NCT02678767	PHASE2	COMPLETED	Ferumoxytol-enhanced Imaging and Mapping in neuroAIDS
NCT03081117	PHASE1/PHASE2	TERMINATED	Intranasal Insulin for the Treatment of HAND
NCT03384784	PHASE2	COMPLETED	Effect of Galantamine on Inflammation and Cognition
NCT00000738	PHASE1	COMPLETED	Randomized, Double-Blind, Placebo-Controlled Trial of Nimodipine for the Neurological Manifestations of HIV-1
NCT00002209	PHASE1	COMPLETED	Safety and Effectiveness of CPI-1189 in HIV-Infected Males on Combination Anti-HIV Drug Therapy
NCT01665846	PHASE1	COMPLETED	Ferumoxytol-enhanced Brain MRI in HIV-associated Neurocognitive Disorders
NCT03581305	PHASE1	COMPLETED	PET Imaging of the Dopaminergic and Serotonergic Systems in Treated HIV Positive Subjects
NCT04330287	Not specified	RECRUITING	HIV-HEART Aging Study
NCT00002044	Not specified	COMPLETED	A Pilot Study To Evaluate the Effect of Retrovir (Zidovudine: AZT) in the Treatment of Human Immunodeficiency Virus (HIV) Associated Dementia and Neuromuscular Diseases
NCT00459693	Not specified	TERMINATED	PET Evaluation of Brain Peripheral Benzodiazepine Receptors Using [11C]PBR28 in HIV-Seropositive Patients With (MCMD)
NCT01434563	Not specified	COMPLETED	The Prevalence of Neurocognitive Disorder in a Primary Care-based HIV Cohort Compared to a HIV-negative Control Cohort -
NCT01547754	Not specified	TERMINATED	Mild Neurocognitive Disorder in HIV Infection of the Brain
NCT02291081	Not specified	COMPLETED	A Prospective Observational Trial to Determine Cardiovascular Diseases in HIV-infected Patients
NCT02431091	Not specified	COMPLETED	Evaluation of the Role of OCT in the Detection of HIV-associated Neurocognitive Disorder
NCT03122288	Not specified	COMPLETED	Individualized Cognitive Training in HIV
NCT03244488	Not specified	COMPLETED	Mental Ability Challenge Study in Adults With and Without HIV
NCT04015830	Not specified	COMPLETED	Exploring Racial Disparities in Sleep Health and Neurocognitive Function
NCT04156048	Not specified	COMPLETED	HIV&HEART Aging Study (12,5 Year Follow up)
NCT04428112	Not specified	COMPLETED	Rural Dementia Caregiver Project
NCT05571761	Not specified	WITHDRAWN	Teleneuropsychological Intervention in Asymptomatic HIV Seropositive Patients: N&C NeuroChange

Drugs tested across these trials (top 30)

Molecule	Max phase	Trials referencing
DARUNAVIR	4	3
MECAMYLAMINE	4	3
FERUMOXYTOL	4	2
ZIDOVUDINE	4	2
ABACAVIR SULFATE	4	1
ATORVASTATIN	4	1
COBICISTAT	4	1
DIDANOSINE	4	1
GALANTAMINE	4	1
MARAVIROC	4	1
NIMODIPINE	4	1
RITONAVIR	4	1
STAVUDINE	4	1
CENICRIVIROC	3	1
CP1-1189	2	1
CHEMBL26318	0	3
CHEMBL4741920	0	1
CHEMBL418334	0	1
CHEMBL2163486	0	1
CHEMBL361331	0	1
CHEMBL5413158	0	1
CHEMBL584744	0	1
CHEMBL39066	0	1
CHEMBL1385	0	1
CHEMBL3764305	0	1
CHEMBL1514440	0	1